FDA Label for Estradiol

Warning: Endometrial Cancer, Cardiovascular Disorders, Breast Cancer And Probable Dementia

Estrogen-Alone Therapy

Endometrial Cancer

There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed

estrogens. Adding a progestin to estrogen therapy has been shown to reduce the risk of

endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic

measures, including directed or random endometrial sampling when indicated, should be

undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or

recurring abnormal genital bleeding [see WARNINGS, Malignant Neoplasms, Endometrial

Cancer].

Cardiovascular Disorders and Probable Dementia

Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or

dementia [see CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders, and

Probable Dementia].

The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of

stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age)

during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg]-alone,

relative to placebo [see CLINICAL STUDIES and WARNINGS, Cardiovascular

Disorders].

The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an

increased risk of developing probable dementia in postmenopausal women 65 years of age or

older during 5.2 years of treatment with daily CE (0.625 mg) -alone, relative to placebo. It is

unknown whether this finding applies to younger postmenopausal women [see CLINICAL

STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use].

In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for

the shortest duration consistent with treatment goals and risks for the individual woman.

Estrogen Plus Progestin Therapy

Cardiovascular Disorders and Probable Dementia

Estrogen plus progestin therapy should not be used for the prevention of cardiovascular

disease or dementia [see CLINICAL STUDIES and WARNINGS, Cardiovascular

Disorders, and Probable Dementia].

The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary

embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79

years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with

medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see CLINICAL

STUDIES and WARNINGS, Cardiovascular Disorders].

The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of

developing probable dementia in postmenopausal women 65 years of age or older during 4

years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see

CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS,

Geriatric Use].

Breast Cancer

The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive

breast cancer [see CLINICAL STUDIES and WARNINGS, Malignant Neoplasms, Breast

Cancer].

In the absence of comparable data, these risks should be assumed to be similar for other

doses of CE and MPA, and other combinations and dosage forms of estrogens and

progestins.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for

the shortest duration consistent with treatment goals and risks for the individual woman.

Description

Each gram of estradiol vaginal cream, USP, 0.01% contains 0.1 mg estradiol in a nonliquefying

base containing purified water, propylene glycol, stearyl alcohol, white ceresin wax, mono- and

di-glycerides, hypromellose 2208 (4000 cps), sodium lauryl sulfate, methylparaben, edetate disodium and tertiary-butylhydroquinone. Estradiol is chemically described as estra-1,3,5(10)-

triene-3, 17(beta)-diol. It has an empirical formula of C18H24O2 and molecular weight of 272.37.

The structural formula is:

Clinical Pharmacology

Endogenous estrogens are largely responsible for the development and maintenance of the

female reproductive system and secondary sexual characteristics. Although circulating estrogens

exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal

intracellular human estrogen and is substantially more potent than its metabolites, estrone and

estriol at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which

secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After

menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted

by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated

form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two

estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone

(LH) and follicle stimulating hormone (FSH), through a negative feedback mechanism.

Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

Pharmacokinetics

Absorption

Estrogen drug products are absorbed through the skin, mucous membranes, and the gastrointestinal tract after release from the drug formulation.

Distribution

The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are

widely distributed in the body and are generally found in higher concentrations in the sex

hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding

globulin (SHBG) and albumin.

Metabolism

Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating

estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations

take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be

converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic

recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates

into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal

women, a significant proportion of the circulating estrogens exist as sulfate conjugates,

especially estrone sulfate, which serves as a circulating reservoir for the formation of more active

estrogens.

Excretion

Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate

conjugates.

Special Populations

No pharmacokinetic studies were conducted in special populations, including patients with renal

or hepatic impairment.

Drug Interactions

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome

P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug

metabolism. Inducers of CYP3A4 such as St. John’s Wort preparations (Hypericum

perforatum), phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of

estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine

bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole,

itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and

may result in side effects.

CLINICAL STUDIES

Women’s Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two

substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination

with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The

primary endpoint was the incidence of coronary heart disease (CHD) (defined as nonfatal MI,

silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A

“global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE,

endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death

due to other cause. These substudies did not evaluate the effects of CE or CE plus MPA on

menopausal symptoms.

WHI Estrogen-Alone Substudy

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was

observed, and it was deemed that no further information would be obtained regarding the risks

and benefits of estrogen-alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age,

range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent

Other), after an average follow-up of 7.1 years are presented in Table 1.

TABLE 1 -Relative and Absolute Risk Seen in the Estrogen-Alone Substudy of WHI^a

For those outcomes included in the WHI "global index" that reached statistical significance, the

absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more

strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures1.

The absolute excess risk of events included in the "global index" was a non-significant 5 events

per 10,000 women-years. There was no difference between the groups in terms of all-cause

mortality.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and

invasive breast cancer incidence in women receiving CE-alone compared with placebo was

reported in final centrally adjudicated results from the estrogen-alone substudy, after an

average follow-up of 7.1 years.

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an

average follow-up of 7.1 years, reported no significant differences in distribution of stroke

subtypes or severity, including fatal strokes, in women receiving CE-alone compared to

placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was

present in all subgroups of women examined².

Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect

the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in

women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio

(HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46–

1.11)].

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was also stopped early. According to the predefined

stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of breast

cancer and cardiovascular events exceeded the specified benefits included in the “global

index.” The absolute excess risk of events included in the “global index” was 19 per 10,000

women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after

5.6 years of follow-up, the absolute excess risks per 10,000 women-years in the group treated

with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive

breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer

colorectal cancers and 5 fewer hip fractures.

Results of the CE plus MPA substudy, which included 16,608 women (average 63 years of age,

range 50 to 79; 83.9 percent White, 6.8 percent Black, 5.4 percent Hispanic, 3.9 percent Other),

are presented in Table 2. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

TABLE 2 -Relative and Absolute Risk Seen in the Estrogen Plus Progestin Substudy of

WHI at an Average of 5.6 Years^{a, b}

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may

affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age

showed in women 50 to 59 years of age, a non-significant trend toward reduced risk for overall

mortality [HR 0.69 (95 percent CI, 0.44-1.07)].

Women’s Health Initiative Memory Study

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy

hysterectomized postmenopausal women 65 to 79 years of age and older (45 percent were

65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of

age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of

probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone

versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of probable dementia for

CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia

as defined in this study included Alzheimer’s disease (AD), vascular dementia (VaD) and mixed

types (having features of both AD and VaD). The most common classification of probable

dementia in the treatment group and the placebo group was AD. Since the ancillary study was

conducted in women 65 to 79 years of age, it is unknown whether these findings apply to

younger postmenopausal women [see BOXED WARNINGS, WARNINGS, Probable

Dementia and PRECAUTIONS, Geriatric Use].

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly

healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of

age; 35 percent were 70 to 74 years; 18 percent were 75 years of age and older) to evaluate

the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia

(primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA

versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk of probable dementia for

CE plus MPA versus placebo was 45 versus 22 per 10,000 women-years. Probable dementia as

defined in this study included AD, VaD and mixed types (having features of both AD and

VaD). The most common classification of probable dementia in the treatment group and the

placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of

age, it is unknown whether these findings apply to younger postmenopausal women [see

WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use].

When data from the two populations were pooled as planned in the WHIMS protocol, the

reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60).

Differences between groups became apparent in the first year of treatment. It is unknown

whether these findings apply to younger postmenopausal women [see WARNINGS, Probable

Dementia and PRECAUTIONS, Geriatric Use].

Indications And Usage

Estradiol vaginal cream, USP, 0.01% is indicated in the treatment of moderate to severe

symptoms of vulvar and vaginal atrophy due to menopause.

Contraindications

Estradiol vaginal cream, USP, 0.01% should not be used in women with any of the following

conditions:

1. Undiagnosed abnormal genital bleeding.

2. Known, suspected, or history of cancer of the breast.

3. Known or suspected estrogen-dependent neoplasia.

4. Active DVT, PE or history of these conditions.

5. Active arterial thromboembolic disease (for example, stroke, MI) or a history of these

conditions.

6. Known anaphylactic reaction or angioedema to estradiol vaginal cream, USP,

0.01%.

7. Known liver dysfunction or disease.

8. Known protein C, protein S, or antithrombin deficiency, or other known

thrombophilic disorders.

9. Known or suspected pregnancy.

Warnings

See BOXED WARNINGS.

Systemic absorption may occur with the use of estradiol vaginal cream, USP, 0.01%. The warnings, precautions, and adverse reactions associated with oral estrogen treatment should be taken into account.

1. Cardiovascular Disorders

An increased risk of stroke and DVT has been reported with estrogen-alone therapy. An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy

should be discontinued immediately.

Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use,

hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (e.g., personal

history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed

appropriately.

a. Stroke

In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was

reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to

women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The

increase in risk was demonstrated in year one and persisted [see CLINICAL STUDIES].

Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued

immediately.

Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for

those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per

10,000 women-years)³.

In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke

was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg)

compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years) [see CLINICAL STUDIES]. The increase in risk was demonstrated after the first year

and persisted³. Should a stroke occur or be suspected, estrogen plus progestin therapy should be

discontinued immediately.

b. Coronary Heart Disease

In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events

(defined as nonfatal MI, silent MI and CHD death) was reported in women receiving estrogen-alone compared to placebo⁴ [see CLINICAL STUDIES].

Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant

reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less

than 10 years since menopause (8 versus 16 per 10,000 women-years)³.

In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased

risk of CHD events reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg)

compared to women receiving placebo (41 versus 34 per 10,000 women-years) 3. An increase in

relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was

reported in years 2 through 5 [see CLINICAL STUDIES].

In postmenopausal women with documented heart disease (n = 2,763), average age 66.7 years of

age, in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and

Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA

(2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years,

treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal

women with established coronary heart disease. There were more CHD events in the CE plus

MPA-treated group than in the placebo group in year 1, but not during the subsequent years.

Two thousand, three hundred and twenty one (2,321) women from the original HERS trial

agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS

II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were

comparable among women in the CE plus MPA group and the placebo group in HERS, HERS II,

and overall.

c. Venous Thromboembolism

In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women

receiving daily CE (0.625 mg)-alone compared to women receiving placebo (30 versus 22 per

10,000 women-years), although only the increased risk of DVT reached statistical significance

(23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the

first 2 years⁵ [see CLINICAL STUDIES]. Should a VTE occur or be suspected, estrogenalone

therapy should be discontinued immediately.

In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of

VTE was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to

women receiving placebo (35 versus 17 per 10,000 women-years). Statistically significant

increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per

10,000 women-years) were also demonstrated. The increase in VTE risk was observed during

the first year and persisted 6[see CLINICAL STUDIES]. Should a VTE occur or be suspected,

estrogen plus progestin therapy should be discontinued immediately.

If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type

associated with an increased risk of thromboembolism, or during periods of prolonged

immobilization.

2. Malignant Neoplasms

a. Endometrial Cancer

An increased risk of endometrial cancer has been reported with the use of unopposed estrogen

therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed

estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on

duration of treatment and on estrogen dose. Most studies show no significant increased risk

associated with use of estrogens for less than one year. The greatest risk appears associated with

prolonged use, with increased risks of 15- to 24-fold for five to ten years or more and this risk

has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is

important. Adequate diagnostic measures, including directed or random endometrial sampling

when indicated, should be undertaken to rule out malignancy in postmenopausal women with

undiagnosed persistent or recurring abnormal genital bleeding.

There is no evidence that the use of natural estrogens results in a different endometrial risk

profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen

therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor

to endometrial cancer.

b. Breast Cancer

The most important randomized clinical trial providing information about breast cancer in

estrogen-alone users is the WHI substudy of daily CE (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE (0.625 mg)-alone was not

associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80)⁷ [see

CLINICAL STUDIES].

The most important randomized clinical trial providing information about breast cancer in

estrogen plus progestin users is the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg).

After a mean follow-up of 5.6 years, the estrogen plus progestin substudy reported an increased

risk of invasive breast cancer in women who took daily CE plus MPA. In this substudy, prior use

of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women.

The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases

per 10,000 women-years, for CE plus MPA compared with placebo. Among women who

reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and

the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared

with placebo. Among women who reported no prior use of hormone therapy, the relative risk of

invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years, for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers

were larger, were more likely to be node positive, and were diagnosed at a more advanced stage

in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic

disease was rare with no apparent difference between the two groups. Other prognostic factors

such as histologic subtype, grade and hormone receptor status did not differ between the groups8

[see CLINICAL STUDIES].

Consistent with the WHI clinical trial, observational studies have also reported an increased risk

of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to

return to baseline in about 5 years after stopping treatment (only the observational studies have

substantial data on risk after stopping). Observational studies also suggest that the risk of breast

cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as

compared to estrogen-alone therapy. However, these studies have not generally found significant

variation in the risk of breast cancer among different estrogen plus progestin combinations,

doses, or routes of administration.

The use of estrogen-alone and estrogen plus progestin therapy has been reported to result in an

increase in abnormal mammograms requiring further evaluation.

All women should receive yearly breast examinations by a healthcare provider and perform

monthly breast self-examinations. In addition, mammography examinations should be scheduled

based on patient age, risk factors, and prior mammogram results.

c. Ovarian Cancer

The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk

of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for

CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77-3.24). The absolute risk for CE plus

MPA was 4 versus 3 cases per 10,000 women-years⁹. In some epidemiologic studies, the use of

estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been

associated with an increased risk of ovarian cancer. However, the duration of exposure

associated with increased risk is not consistent across all epidemiologic studies, and some report

no association.

3. Probable Dementia

In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized

women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.

After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in

the placebo group were diagnosed with probable dementia. The relative risk of probable

dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83-2.66). The absolute risk of

probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years

¹⁰ [see CLINICAL STUDIES and PRECAUTIONS, Geriatric Use].

In the WHIMS estrogen plus progestin ancillary study, a population of 4,532 postmenopausal

women 65 to 79 years of age was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or

placebo.

After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in

the placebo group were diagnosed with probable dementia. The relative risk of probable

dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21-3.48). The absolute risk

of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000

women-years¹⁰ [see CLINICAL STUDIES and PRECAUTIONS, Geriatric Use].

When data from the two populations in the WHIMS estrogen-alone and estrogen plus progestin

ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative

risk for probable dementia was 1.76 (95 percent CI, 1.19-2.60). Since both ancillary studies were

conducted in women 65 to 79 years of age, it is unknown whether these findings apply to

younger postmenopausal women 10 [see PRECAUTIONS, Geriatric Use].

4. Gallbladder Disease

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal

women receiving estrogens has been reported.

5. Hypercalcemia

Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and

bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate

measures taken to reduce the serum calcium level.

6. Visual Abnormalities

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue

medication pending examination if there is sudden partial or complete loss of vision, or a sudden

onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular

lesions, estrogens should be permanently discontinued.

7. Anaphylactic Reaction and Angioedema

Cases of anaphylaxis, which develop within minutes to hours after taking orally-administered

estrogen and require emergency medical management, have been reported in the postmarketing

setting. Skin (hives, pruritis, swollen lips-tongue-face) and either respiratory tract (respiratory

compromise) or gastrointestinal tract (abdominal pain, vomiting) involvement has been noted.

Angioedema involving the tongue, larynx, face, hands and feet requiring medical intervention

has occurred postmarketing in patients taking orally-administered estrogen. If angioedema

involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop an

anaphylactic reaction with or without angioedema after treatment with oral estrogen should not

receive oral estrogen again.

8. Hereditary Angioedema

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary

angioedema.

Precautions

A. General

1. Addition of a Progestin When a Woman Has Not Had a Hysterectomy

Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration,

or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial

hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be

a precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestins with

estrogens compared to estrogen-alone regimens. These include a possible increased risk of

breast cancer.

2. Elevated Blood Pressure

In a small number of case reports, substantial increases in blood pressure have been attributed to

idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a

generalized effect of estrogens on blood pressure was not seen.

3. Hypertriglyceridemia

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with

elevations of plasma triglycerides leading to pancreatitis and other complications. Consider

discontinuation of treatment if pancreatitis occurs.

4. Hepatic Impairment and/or Past History of Cholestatic Jaundice

Estrogens may be poorly metabolized in patients with impaired liver function. For women with

a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution

should be exercised and in the case of recurrence, medication should be discontinued.

5. Hypothyroidism

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with

normal thyroid function can compensate for the increased TBG by making more thyroid

hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women

dependent on thyroid hormone replacement therapy who are also receiving estrogens may

require increased doses of their thyroid replacement therapy. These women should have their

thyroid function monitored in order to maintain their free thyroid hormone levels in an

acceptable range.

6. Fluid Retention

Estrogens may cause some degree of fluid retention. Women with conditions that might be

influenced by this factor, such as a cardiac or renal dysfunction, warrant careful observation

when estrogen- alone is prescribed.

7. Hypocalcemia

Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.

8. Exacerbation of Endometriosis

A few cases of malignant transformation of residual endometrial implants have been reported in

women treated post-hysterectomy with estrogen alone therapy. For patients known to have

residual endometriosis post-hysterectomy, the addition of progestin should be considered.

9. Exacerbation of Other Conditions

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or

porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with

caution in women with these conditions.

B. Patient Information

Physicians are advised to discuss the PATIENT INFORMATION leaflet with women for whom

they prescribe estradiol vaginal cream, USP, 0.01%.

C. Laboratory Tests

Serum FSH and estradiol levels have not been shown to be useful in the management of

moderate to severe symptoms of vulvar and vaginal atrophy.

D. Drug-Laboratory Test Interactions

1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time;

increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant

activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin;

decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III

activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen

antigen and activity.

2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid

hormone levels, as measured by protein-bound iodine (PBI), T4 levels (by column or by

radioimmunoassay) or T3 levels by radioimmunoassay. T3 resin uptake is decreased,

reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on

thyroid replacement therapy may require higher dose of thyroid hormone.

3. Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin

(CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating

corticosteroids and sex steroids, respectively. Free hormone concentrations, such as

testosterone and estradiol, may be decreased. Other plasma proteins may be increased

(angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

4. Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction

concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration,

increased triglycerides levels.

5. Impaired glucose tolerance.

E. Carcinogenesis, Mutagenesis, and Impairment of Fertility

Long-term continuous administration of estrogen, with and without progestin, in women with

and without a uterus, has shown an increased risk of endometrial cancer, breast cancer, and

ovarian cancer. [See BOXED WARNINGS, WARNINGS and PRECAUTIONS.]

Long term continuous administration of natural and synthetic estrogens in certain animal species

increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

F. Pregnancy

Estradiol vaginal cream, USP, 0.01% should not be used during pregnancy [see

CONTRAINDICATIONS].

There appears to be little or no increased risk of birth defects in children born to women who

have used estrogens and progestins as an oral contraceptive inadvertently during early

pregnancy.

G. Nursing Mothers

Estradiol vaginal cream, USP, 0.01% should not be used during lactation. Estrogen

administration to nursing women has been shown to decrease the quantity and quality of the

breast milk. Detectable amounts of estrogens have been identified in the milk of women

receiving estrogen therapy. Caution should be exercised when estradiol vaginal cream, USP,

0.01% is administered to a nursing woman.

H. Pediatric Use

Estradiol vaginal cream, USP, 0.01% is not indicated in children. Clinical studies have not been

conducted in the pediatric population.

I. Geriatric Use

There have not been sufficient numbers of geriatric patients involved in studies utilizing estradiol

vaginal cream, USP, 0.01% to determine whether those over 65 years of age differ from younger

subjects in their response to estradiol vaginal cream, USP, 0.01%.

The Women’s Health Initiative Study

In the WHI estrogen-alone substudy (daily CE [0.625 mg]-alone versus placebo), there was

a higher relative risk of stroke in women greater than 65 years of age [see CLINICAL

STUDIES and WARNINGS].

In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg]

versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast

cancer in women greater than 65 years of age [see CLINICAL STUDIES and

WARNINGS].

The Women’s Health Initiative Memory Study

In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there

was an increased risk of developing probable dementia in women receiving estrogen-alone

or estrogen plus progestin when compared to placebo [see CLINICAL STUDIES and

WARNINGS].

Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown

whether these findings apply to younger postmenopausal women 10 [see CLINICAL

STUDIES and WARNINGS].

Adverse Reactions

See BOXED WARNINGS, WARNINGS and PRECAUTIONS.

Systemic absorption may occur with the use of estradiol vaginal cream, USP, 0.01%. The

warnings, precautions, and adverse reactions associated with oral estrogen treatment should

be taken into account.

The following adverse reactions have been reported with estrogen and/or progestin therapy.

1. Genitourinary System

Abnormal uterine bleeding or spotting; dysmenorrhea or pelvic pain, increase in size of uterine

leiomyomata; vaginitis, including vaginal candidiasis; change in cervical secretion; cystitis-like

syndrome; application site reactions of vulvovaginal discomfort including burning and irritation;

genital pruritus; ovarian cancer; endometrial hyperplasia; endometrial cancer.

2. Breasts

Tenderness, enlargement, pain, nipple discharge, fibrocystic breast changes; breast cancer.

3. Cardiovascular

Deep and superficial venous thrombosis; pulmonary embolism; myocardial infarction; stroke;

increase in blood pressure.

4. Gastrointestinal

Nausea, vomiting; abdominal cramps, bloating; increased incidence of gallbladder disease.

5. Skin

Chloasma that may persist when drug is discontinued; loss of scalp hair; hirsutism; rash.

6. Eyes

Retinal vascular thrombosis, intolerance to contact lenses.

7. Central Nervous System

Headache; migraine; dizziness; mental depression; nervousness; mood disturbances; irritability;

dementia.

8. Miscellaneous

Increase or decrease in weight; glucose intolerance; edema; arthralgias; leg cramps; changes in

libido; urticaria; exacerbation of asthma; increased triglycerides; hypersensitivity (including

erythema multiforme).

Overdosage

Overdosage of estrogen may cause nausea, vomiting, breast tenderness, abdominal pain,

drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose

consists of discontinuation of estradiol vaginal cream, USP, 0.01% therapy together with

institution of appropriate symptomatic care.

Dosage And Administration

Use of estradiol vaginal cream, USP, 0.01% alone or in combination with a progestin, should be

limited to the shortest duration consistent with treatment goals and risks for the individual

woman. Postmenopausal women should reevaluate periodically as clinically appropriate to

determine if treatment is still necessary. For treatment of vulvar and vaginal atrophy associated

with the menopause, the lowest dose and regimen that will control symptoms should be chosen

and medication should be discontinued as promptly as possible. For women who have a uterus,

adequate diagnostic measures, including directed and random endometrial sampling when

indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or

recurring abnormal genital bleeding.

Usual Dosage: The usual dosage range is 2 to 4 g (marked on the applicator) daily for one or two

weeks, then gradually reduced to one half initial dosage for a similar period. A maintenance

dosage of 1 g, one to three times a week, may be used after restoration of the vaginal mucosa has

been achieved.

NOTE: The number of doses per tube will vary with dosage requirements and patient

handling.

How Supplied

Estradiol Vaginal Cream, USP, 0.01%.

NDC 0093-3541-43: Tube containing 1 ½ oz (42.5 g) with a calibrated plastic applicator for

delivery of 1, 2, 3, or 4 g.

Store at room temperature 20° to 25°C (59° to 77°F). Protect from temperatures in excess

of 40°C (104° F).

Keep Estradiol Vaginal Cream, USP, 0.01% out of the reach of children.

References

1. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in

Postmenopausal Women With Hysterectomy: Results From the Women’s Health Initiative

Randomized Trial. J Bone Miner Res. 2006;21:817-828.

2. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women’s Health

Initiative. Circulation. 2006;113:2425-2434.

3. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by

Age and Years Since Menopause. JAMA. 2007;297:1465-1477.

4. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med.

2006;166:357-365.

5. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a

Uterus. Arch Int Med. 2006;166:772-780.

6. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA.

2004;292:1573-1580.

7. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and

Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA.

2006;295:1647-1657.

8. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and

Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.

9. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and

Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748.

10. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and

Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:29472958.

Manufactured In Canada by:

Contract Pharmaceuticals Limited

Mississauga, Ontario, Canada L5N 6L6

Distributed By:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

1-888-838-2872

Rev. B 05/2017

Information For The Patient

Estradiol Vaginal Cream, USP, 0.01%

Rx only

INFORMATION FOR THE PATIENT

Read this PATIENT INFORMATION before you start using estradiol vaginal cream, USP,

0.01% and read what you get each time you refill your estradiol vaginal cream, USP, 0.01%

prescription. There may be new information. This information does not take the place of

talking with your healthcare provider about your menopausal symptoms or your treatment.

What is Estradiol Vaginal Cream, 0.01%?

Estradiol Vaginal Cream, 0.01% is a medicine that contains an estrogen hormone.

What is Estradiol Vaginal Cream, 0.01% used for?

Estradiol Vaginal Cream, 0.01% is used after menopause to:

• Treat moderate to severe menopausal changes in and around the vagina

You and your healthcare provider should talk regularly about whether you still need treatment with estradiol vaginal cream, 0.01% to control these problems.

Who should not use Estradiol Vaginal Cream, 0.01%?

Do not start using estradiol vaginal cream, 0.01% if you:

• Have unusual vaginal bleeding

• Currently have or have had certain cancers

Estrogens may increase the chances of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your healthcare provider about whether you should use estradiol vaginal cream, 0.01%.

• Had a stroke or heart attack

• Currently have or have had blood clots

• Currently have or have had liver problems

• Have been diagnosed with a bleeding disorder

• Are allergic to estradiol vaginal cream, 0.01% or any of its ingredients

See the list of ingredients in estradiol vaginal cream, 0.01% at the end of this leaflet.

• Think you may be pregnant

Tell your healthcare provider:

• If you have unusual vaginal bleeding

Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.

• About all of your medical problems

Your healthcare provider may need to check you more carefully if you have certain conditions, such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.

• About all the medicines you take

This includes prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how estradiol vaginal cream, 0.01% works. Estradiol vaginal cream, 0.01% may also affect how your other medicines work.

• If you are going to have surgery or will be on bed rest.

You may need to stop using estradiol vaginal cream, 0.01%.

• If you are breastfeeding

The estrogen hormone in estradiol vaginal cream, 0.01% can pass into your breast milk.

How should I use Estradiol Vaginal Cream, 0.01%?

Estradiol vaginal cream, 0.01% is a cream that you place in your vagina with the applicator

provided with the cream.

• Take the dose recommended by your healthcare provider and talk to him or her about how well that dose is working for you

• Estrogens should be used at the lowest dose possible for your treatment only as long as needed. You and your healthcare provider should talk regularly (for example, every 3 to 6 months) about the dose you are using and whether you still need treatment with estradiol vaginal cream, 0.01%

• Step 1. Remove the cap from the tube. (There is no seal on tube)

• Step 2. Do not separate plunger from applicator.

• Step 3. Screw threaded end of applicator onto the open tube until secure.

• Step 4. Position upright in order to view the calibrated gram amounts.

• Step 5. Gently squeeze tube from the bottom to expel the prescribed amount of estradiol vaginal cream, 0.01% into the applicator. As cream is squeezed out, plunger will rise to indicate amount of grams.

• Step 6. Unscrew applicator from tube.

• Step 7. Replace cap on tube.

• Step 8. Lie on back with knees drawn up. To deliver medication, gently insert applicator deeply into vagina and press plunger downward to its original position.

• Step 9. To cleanse applicator: Pull plunger to remove it from barrel. Wash with mild soap and warm water (DO NOT BOIL OR USE HOT WATER)

What are the possible side effects of Estradiol Vaginal Cream, 0.01%?

Although estradiol vaginal cream, 0.01% is only used in and around the vagina, the risks

associated with oral estrogens should be taken into account.

Side effects are grouped by how serious they are and how often they happen when you are

treated.

Serious, but less common side effects include:

• Heart attack

• Stroke

• Blood clots

• Dementia

• Breast cancer

• Cancer of the lining of the uterus (womb)

• Cancer of the ovary

• High blood pressure

• High blood sugar

• Gallbladder disease

• Liver problems

• Enlargement of benign tumors of the uterus (“fibroids”)

• Severe allergic reaction

Call your healthcare provider right away if you get any of the following warning signs or

any other unusual symptoms that concern you:

• New breast lumps

• Unusual vaginal bleeding

• Changes in vision or speech

• Sudden new severe headaches

• Severe pains in your chest or legs with or without shortness of breath, weakness and fatigue

• Swollen lips, tongue or face

Less serious, but common side effects include:

• Headache

• Breast pain

• Irregular vaginal bleeding or spotting

• Stomach or abdominal cramps, bloating

• Nausea and vomiting

• Hair loss

• Fluid retention

• Vaginal yeast infection

• Reactions from inserting estradiol vaginal cream, 0.01%, such as vaginal burning, irritation, and itching

These are not all the possible side effects of estradiol vaginal cream, 0.01%. For more information, ask your healthcare provider or pharmacist for advice about side effects. You may

report side effects to FDA at 1-800-FDA-1088.

What can I do to lower my chances of a serious side effect with Estradiol Vaginal Cream,

0.01%?

• Talk with your healthcare provider regularly about whether you should continue using estradiol vaginal cream, 0.01%.

• If you have a uterus, talk with your healthcare provider about whether the addition of a progestin is right for you. The addition of a progestin is generally recommended for a woman with a uterus to reduce the chance of getting cancer of the uterus.

• See your healthcare provider right away if you get vaginal bleeding while using estradiol vaginal cream, 0.01%.

• Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your

healthcare provider tells you something else. If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.

• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease.

Ask your healthcare provider for ways to lower your chances for getting heart disease.

General information about safe and effective use of Estradiol Cream, 0.01%

Medicines are sometimes prescribed for conditions that are not mentioned in patient information

leaflets. Do not use estradiol vaginal cream, 0.01% for conditions for which it was not prescribed. Do not give estradiol vaginal cream, 0.01% to other people, even if they have the

same symptoms you have. It may harm them.

Keep estradiol vaginal cream, 0.01% out of the reach of children.

This leaflet provides a summary of the most important information about estradiol vaginal

cream, 0.01%. If you would like more information, talk with your healthcare provider or

pharmacist. You can ask for information about estradiol vaginal cream, 0.01% that is written

for health professionals. You can get more information by calling the toll free number 1-866-

832-8537.

What are the ingredients in Estradiol Vaginal Cream, 0.01%?

Each gram of estradiol vaginal cream, 0.01% contains 0.1 mg estradiol in a nonliquefying

base containing purified water, propylene glycol, stearyl alcohol, white ceresin wax, monoand

di- glycerides, hypromellose 2208 (4000 cps), sodium lauryl sulfate, methylparaben,

edetate di- sodium and tertiary-butylhydroquinone.

HOW SUPPLIED

Estradiol Vaginal Cream, 0.01%.

NDC 0093-3541-43: Tube containing 1 ½ oz (42.5 gram) with a calibrated plastic applicator for

delivery of 1, 2, 3, or 4 gram.

NOTE: The number of doses per tube will vary with dosage requirements and patient

handling.

Store at room temperature 20° to 25°C (59° to 77°F). Protect from temperatures in excess

of 40° C (104° F).

Manufactured In Canada by:

Contract Pharmaceuticals Limited

Mississauga, Ontario, Canada L5N 6L6

Distributed By:

Teva Pharmaceuticals USA, Inc.

North Wales, PA 19454

1-888-838-2872

Rev. B 05/2017

Estradiol Vaginal Cream Usp 0.01% Unscented, 42.5 G Carton Text

NDC 0093-3541-43

Estradiol Vaginal Cream USP

0.01%

UNSCENTED

Each gram contains 0.1 mg estradiol in a nonliquefying base.

Usual Dosage: See enclosed Package Insert for Full Prescribing Information.

CAUTION: Keep this and all medications out of the reach of children.

CALIBRATED APPLICATOR ENCLOSED

This product also contains purified water, propylene glycol, stearyl alcohol,

white ceresin wax, mono- and di-glycerides, hypromellose, sodium lauryl

sulfate, methylparaben, edetate disodium, and t-butylhydroquinone.

Read Accompanying Information For The Patient

SHAPING

WOMEN’S HEALTH®

Rx only

NET WT 1 ½ OZ *42.5 G) TUBE

TEVA